1. Field of the Invention
The present invention generally relates to a formulation used to decrease the incidence of secondary hemorrhage after hyphema and, more particularly, to a topical formulation which includes aminocaproic acid which is applied to a patient's eye.
2. Description of the Prior Art
Injuries caused by a blow to the eye are referred to as hyphema. These injuries include puncture wounds, such as would occur with a pencil or nail, as well as wounds resulting from the impact of a hard object, such as a baseball or racquetball. Secondary hemorrhage is a serious complication of traumatic hyphema where a rebleed at the injured site occurs. When a patient experiences a secondary hemorrhage, the rebleeding generally occurs within two to five days after the initial injury. Secondary hemorrhage is usually more severe than the initial hemorrhage and significantly worsens the prognosis of an already traumatized eye. Secondary hemorrhage occurs in 18% to 38% of traumatic hyphemas, and the overall incidence is approximately 25%. With secondary bleeding, the incidence of glaucoma increases to 50%, and there is a much greater chance of corneal blood staining and optic atrophy.
An oral form of .epsilon.-Aminocaproic acid (ACA) developed in the mid-1970s has been shown to significantly reduce the incidence of secondary hemorrhage. ACA is an antifibrinolytic agent and functions by inhibiting plasminogen activity, thereby reducing the tame of enzymatic breakdown of a clot. The typical dosage of oral ACA ranges from 50 mg/kg per dose to 100 mg/kg per dose. A drawback of orally delivered ACA is that administration of the drug is required every four hours. More importantly, many adverse affects have been observed when ACA is provided orally or by other systemic routes (e.g., peritoneal or intravenous injection). Specifically, patients have been reported to experience nausea and vomiting, dizziness, systemic hypotension, and syncopal episodes. Vomiting is one of the worst side effects of orally administered ACA because vomiting puts pressure on the eye which may actually cause a secondary hemorrhage. Although decreasing the dose of aminocaproic acid (50 mg/kg per dose) appears to decrease the incidence of some of these adverse effects, many ophthalmologists are still reluctant to institute treatment with systemic ACA.
Loewy et al., Arch. Ophthalmol., 105:272-276 (1987) reported studies of the plasma and aqueous humor pharmacodynamics of intravenously administered ACA. Peak aqueous humor ACA levels of 1.3 and 3.3 mg/dL were obtained after administration of 50- and 100-mg/kg intravenous boluses, respectively. When ACA was given by infusion at 25 mg/kg/h, the peak concentration was 0.25 mg/dL in the aqueous humor. Plasma concentrations ranged from 3.5 mg/dL (infusion, 25 mg/kg/h) to 25.5 mg/dL (100 mg/kg bolus). Antifibrinolytic activity was found to parallel ACA concentrations in both the plasma and the aqueous humor.
Allingham et al., Archives of Ophthalmology, 105:1421-1423 (1987), reported that polyvinyl alcohol and carboxypolymethylene, a carbomer gel and hydrophilic polymer referred to hereinafter as carbopol, are good vehicles for providing ACA to the aqueous humor by topical administration. Specifically, it was found that ACA dissolves in these vehicles, and that solutions of polyvinyl alcohol with 735 g/L of ACA and carbopol with 600 g/L of ACA which were topically applied to the eyes of test rabbits resulted in ACA levels in the aqueous humor comparable to those obtained by intravenous infusion (25 mg/kg/h). Most notably, the plasma levels in the rabbits treated with the topical ACA preparations were 5 to 33% of those observed in Loewy et al. with intravenous ACA administration. Hence, it was suggested that topically applied ACA could be developed to treat traumatic hyphema since suitable ACA levels could be achieved in the aqueous humor with reduced systemic side effects since systemic ACA levels with the topically applied ACA were significantly reduced.
Allingham et al., Archives of Ophthalmology, 106:1436-1438 (1988), reported that topically applied aminocaproic acid significantly reduces the incidence of secondary hemorrhage in traumatic hyphema in the rabbit model. In the study, rabbits with experimentally induced traumatic hyphemas were treated with topical placebo (4% carbopol gel only) and with carbopol gel containing ACA. In the control and placebo groups, there was a 33% rebleed rate, while in the treated eyes there was only a 10% rebleed rate which was statistically significant. No evidence of systemic toxicity was observed in the rabbits. In addition, in the study, droplets of 0.5% proparacaine were provided to the rabbit eyes prior to installation of the gels. Proparacaine is a local anesthetic that can increase corneal penetration of ACA.
Ehlers et al., Ophthalmology & Visual Science. 31:2389-2394 (1990), reported studies related to optimized topical ACA formulations and dosing schedules in the rabbit model. In the studies, the ACA concentration in the topical formulations was varied from 15% to 60% and the carbopol gel vehicle concentration was varied from 0.5% to 4%. In addition, the dose size, frequency of dosing, the effects of pretreatment with topical anesthetics, and the effect of simulated patching of the eye were examined. It was determined that the optimum topical regimen in the rabbit model was 200 .mu.l of 30% ACA in 2% carbopol every six hours in unpatched eyes. The administration of proparacaine droplets prior to instilling the topical ACA containing gel was found to significantly enhance the penetration of ACA in the aqueous humor.
The above studies, all of which were conducted under the supervision of the joint-inventors of this patent application, Dr. Crouch and Dr. Williams, show that a topical formulation of aminocaproic acid would be superior to the orally delivered drug since the adverse systemic side effects would be avoided. Nevertheless, formulating a suitable topical ACA gel for clinical use on human beings poses considerable challenges. Achieving a pH in the gel where the pH throughout the gel is uniform is required for safety in topical ophthalmic products. In addition, suitable topical gels must have a solubility and consistency which allows spreading the ACA gel over the corneal epithelium without losing contact with the corneal epithelium. Furthermore, achieving sterility of the ophthalmic product is required, but difficult to achieve with a gel since filter sterilization and heat sterilization techniques cannot be used. Moreover, despite the fact that the earlier work was performed with rabbits, the earlier work does not disclose a product formulation suitable for use on animals by a veterinarian since the problems of pH, solubility and consistency, and sterility remain a concern.